Neurobehavioral effects of acute exposure to isoparaffinic and cycloparaffinic hydrocarbons.

This article reports neurobehavioral tests in rats with C5-C11 isoparaffinic and cycloparaffinic hydrocarbons. Testing, conducted shortly after exposure, evaluated the effects in several domains including clinical effects, motor activity, functional observations, and visual discrimination performance. Isopentane and cyclopentane did not produce any evidence of acute central nervous system (CNS) effects at levels up to 20 000 mg/m(3). A C(6)/C(7) mixed cycloparaffinic solvent produced minor, reversible changes in latency to response in visual discrimination testing at 14 000 mg/m(3); the no-effect level was 4200 mg/m(3). A C(8) isoparaffin produced no effects at 14 000 mg/m(3), the highest level tested. A C(9)/C(11) isoparaffinic solvent produced minor acute CNS effects at 5000 mg/m(3), with 1500 mg/m(3) as the no-effect level. A C(10) cycloparaffinic solvent did not produce any statistically significant CNS effects at 5000 mg/m(3). These studies were designed to provide data that may be useful in setting occupational exposure limits for C5-C11 isoparaffinic and cycloparaffinic hydrocarbons.

Neurobehavioral effects of acute exposure to normal (n-) paraffins.

This article reports the results of neurobehavioral tests on C(5)-C(10) normal paraffinic constituents (n-paraffins). Shortly after exposure, effects were evaluated in several domains including clinical effects, motor activity, functional observations, and visual discrimination performance. The representative C(5) n-paraffin, n-pentane, did not produce any evidence of acute central nervous system (CNS) effects at levels up to 20 000 mg/m(3). Similarly, there was no compelling evidence that n-octane (C(8)) produced CNS effects at 14 000 mg/m(3), the highest concentration tested. n-decane (C(10)) produced minor, reversible acute CNS effects at 5000 mg/m(3), with 1500 mg/m(3) as the no-effect level. Consistent with literature data, there seemed to be a relationship between increasing molecular weight up to C(10) and acute CNS effects. However, the CNS effects were reversible. Repeated exposures did not provide evidence of metabolic induction.

Neurobehavioral effects of acute exposure to aromatic hydrocarbons.

This article reports the results of neurobehavioral tests on representative aromatic constituents, specifically C(9) to C(11) species. The testing evaluated effects in several domains including clinical effects, motor activity, functional observations, and visual discrimination performance. Exposures ranging from 600 to 5000 mg/m(3), depending on the molecular weights of the specific aromatic constituents, produced minor, reversible effects on the central nervous system (CNS), particularly in the domains of gait and visual discrimination. There was little evidence of effects at lower exposure levels. There was some evidence of respiratory effects at 5000 mg/m(3) in 1 study, and there were also minor changes in body weight and temperature. The CNS effects became less pronounced with repeated exposures, corresponding to lower concentrations in the brain of 1 representative substance, 1,2,4-trimethyl benzene (TMB). At high exposure levels, the alkyl benzenes apparently induced their own metabolism, increasing elimination rates.

Neurobehavioral effects of cyclohexane in rat and human.

The neurobehavioral effects of inhaled cyclohexane in rats and humans are investigated to define relationships between internal doses and acute central nervous system effects. Rats are exposed for 3 consecutive days at target concentrations of 0, 1.4, 8, and 28 g/m(3), 8 h/d. Measurements include standardized observational measures, spontaneous motor activity assessments, and learned visual discrimination performance. Cyclohexane concentrations in blood and brain are measured to assess internal exposure. Human volunteers are exposed for 4 hours to 86 or 860 mg/m(3) in 2 test sessions. Neurobehavioral effects are measured using a computerized neurobehavioral test battery. In rats, there are slight reductions in psychomotor speed in the high-exposure group but minimal central nervous system effects. In humans, there are no significant treatment-related effects at the levels tested.

Physiologically based pharmacokinetic modeling of cyclohexane as a tool for integrating animal and human test data.

This report describes a physiologically based pharmacokinetic model for cyclohexane and its use in comparing internal doses in rats and volunteers following inhalation exposures. Parameters describing saturable metabolism of cyclohexane are measured in rats and used along with experimentally determined partition coefficients. The model is evaluated by comparing predicted blood and brain concentrations to data from studies in rats and then allometrically scaling the results to humans. Levels of cyclohexane in blood and exhaled air are measured in human volunteers and compared with model values. The model predicts that exposure of volunteers to cyclohexane at levels of 4100 mg/m(3) ( approximately 1200 ppm) will result in brain levels similar to those in rats exposed to 8000 mg/m(3) (the no-effect level for acute central nervous system effects). There are no acute central nervous system effects in humans exposed to 860 mg/m(3), consistent with model predictions that current occupational exposure levels for cyclohexane protect against acute central nervous system effects.

Model studies for evaluating the neurobehavioral effects of complex hydrocarbon solvents III. PBPK modeling of white spirit constituents as a tool for integrating animal and human test data.

As part of a project designed to develop a framework for extrapolating acute central nervous system (CNS) effects of hydrocarbon solvents in animals to humans, experimental studies were conducted in rats and human volunteers in which acute CNS effects were measured and toxicokinetic data were collected. A complex hydrocarbon solvent, white spirit (WS) was used as a model solvent and two marker compounds for WS, 1,2,4-trimethyl benzene (TMB) and n-decane (NDEC), were analyzed to characterize internal exposure after WS inhalation. Toxicokinetic data on blood and brain concentrations of the two marker compounds in the rat, together with in vitro partition coefficients were used to develop physiologically based pharmacokinetic (PBPK) models for TMB and NDEC. The rat models were then allometrically scaled to obtain models for inhalatory exposure for man. The human models were validated with blood and alveolar air kinetics of TMB and NDEC, measured in human volunteers. Using these models, it was predicted that external exposures to WS in the range of 344-771mg/m(3) would produce brain concentrations similar to those in rats exposed to 600mg/m(3) WS, the no effect level (NOEL) for acute CNS effects. Assuming similar brain concentration-effect relations for humans and rats, the NOEL for acute CNS effects in humans should be in this range. The prediction was consistent with data from a human volunteer study in which the only statistically significant finding was a small change in the simple reaction time test following 4h exposure to approximately 570mg/m(3) WS. Thus, the data indicated that the results of animal studies could be used to predict a no effect level for acute CNS depression in humans, consistent with the framework described above.

Model studies for evaluating the neurobehavioral effects of complex hydrocarbon solvents II. Neurobehavioral effects of white spirit in rat and human.

To evaluate the neurobehavioral effects of hydrocarbon solvents and to establish a working model for extrapolating animal test data to humans, studies were conducted which involved inhalation exposure of rats and humans to white spirit (WS). The specific objectives of these studies were to evaluate the behavioral effects of exposure to WS in rats and humans and to determine relationships between internal levels of exposure and behavioral effects. In both animals and volunteers, methods for assessment of similar functional effects were used to enable interspecies comparisons. A battery of tests including standardized observational measures, spontaneous motor activity assessments and learned visual discrimination performance was utilized in rat studies to evaluate acute central nervous system (CNS) depression. Groups of rats were exposed to WS at target concentrations of 0, 600, 2400 or 4800mg/m(3), 8h/day for 3 consecutive days. Blood and brain concentrations of two WS constituents; 1,2,4-trimethylbenzene (TMB) and n-decane (NDEC), were used as biomarkers of internal exposure. In a volunteer study, 12 healthy male subjects were exposed for 4h to either 57 or 570mg/m(3) WS in two test sessions spaced 7 days apart, and neurobehavioral effects were measured using a computerized neurobehavioral test battery. Blood samples were taken at the end of the exposure period to measure internal concentrations of TMB and NDEC. Results of the behavioral tests in rats indicated WS-induced changes particularly in performance and learned behavior. In humans, some subtle performance deficits were observed, particularly in attention. The behavioral effects were related to concentrations of the WS components in the central nervous system. These studies demonstrated a qualitative similarity in response between rats and humans, adding support to the view that the rodent tests can be used to predict levels of response in humans and to assist in setting occupational exposure levels for hydrocarbon solvents.

Model studies for evaluating the acute neurobehavioral effects of complex hydrocarbon solvents I. Validation of methods with ethanol.

As a preliminary step to evaluating the acute neurobehavioral effects of hydrocarbon solvents and to establish a working model for extrapolating animal test data to humans, joint neurobehavioral/toxicokinetic studies were conducted which involved administering ethanol to rats and volunteers. The specific objectives of the present studies were to evaluate the acute central nervous system (CNS) effects of ethanol in rats and humans and to assess relationships between internal levels of exposure and behavioral effects. A more general objective was to validate a battery of neurobehavioral tests that could be used to carry out comparative studies in both species. Accordingly, a range of tests including standardized observational measures, spontaneous motor activity assessments and learned visual discrimination performance was utilized in rat studies to evaluate acute CNS effects. Groups of rats were given ethanol at levels of approximately 0.5, 1.0 or 2.0g/kg, with blood level measurements to verify internal doses. In a volunteer study, 12 healthy male subjects were given 0.65g/kg ethanol, a level approximating the limit for motor vehicle operation in The Netherlands, and neurobehavioral effects were measured prior to and 1 and 3h after ethanol administration, with a computerized neurobehavioral test battery. Blood and air measurements were made to quantify internal doses. Results of the behavioral tests in rats provided evidence of ethanol-induced changes in neuromuscular, sensori-motor, and activity domains. There were also significant changes in visual discrimination, particularly in the areas of general measures of responding and psychomotor speed. In humans there were small but statistically significant effects on learning and memory, psychomotor skills and attention. However, the effects were subtle and not all parameters within given domains were affected. These studies demonstrated a qualitative similarity in response between rats and humans.

An analysis of human response to the irritancy of acetone vapors.

Studies on the irritative effects of acetone vapor in humans and experimental animals have revealed large differences in the lowest acetone concentration found to be irritative to the respiratory tract and eyes. This has brought on much confusion in the process of setting occupational exposure limits for acetone. A literature survey was carried out focusing on the differences in results between studies using subjective (neuro)behavioral methods (questionnaires) and studies using objective measurements to detect odor and irritation thresholds. A critical review of published studies revealed that the odor detection threshold of acetone ranges from about 20 to about 400 ppm. Loss of sensitivity due to adaptation and/or habituation to acetone odor may occur, as was shown in studies comparing workers previously exposed to acetone with previously unexposed subjects. It further appeared that the sensory irritation threshold of acetone lies between 10,000 and 40,000 ppm. Thus, the threshold for sensory irritation is much higher than the odor detection limit, a conclusion that is supported by observations in anosmics, showing a ten times higher irritation threshold level than the odor threshold found in normosmics. The two-times higher sensory irritation threshold observed in acetone-exposed workers compared with previously nonexposed controls can apart from adaptation be ascribed to habituation. An evaluation of studies on subjectively reported irritation at acetone concentrations < 1000 ppm shows that perception of odor intensity, information bias, and exposure history (i.e., habituation) are confounding factors in the reporting of irritation thresholds and health symptoms. In conclusion, subjective measures alone are inappropriate for establishing sensory irritation effects and sensory irritation threshold levels of odorants such as acetone. Clearly, the sensory irritation threshold of acetone should be based on objective measurements.

Effects of exposure to trichloroethylene and noise on hearing in rats.

Four groups of rats (n=8 per group) were exposed to either 3000 ppm trichloroethylene (TCE) alone or to 95 dB SPL noise alone or to the combination of TCE and noise or to control conditions. Exposure was carried out 18 hours/day, 5 days/week for 3 weeks. Exposure to TCE alone resulted in hearing loss at 4, 8, 16 and 20 kHz, but not at 24 and 32 kHz. Hearing loss due to exposure to noise alone occurred at frequencies of 8, 16 and 20 kHz. In general, combined exposure to TCE and noise resulted in larger auditory threshold changes than that produced by either TCE alone or noise alone when measured 1 and 2 weeks after the completion of exposure. For frequencies of 8, 16 and 20 kHz, hearing loss due to combined TCE-noise exposure was not larger than the algebraic sum of hearing loss due to exposure to TCE or noise alone. However, at a frequency of 4 kHz, hearing loss due to combined exposure was significantly larger than that produced by TCE exposure alone or noise alone, which itself had no effect at this frequency. These results suggest evidence of an interaction of combined exposure to TCE and noise at the lower edge of the range of frequencies affected.